key: cord-0270943-udynxh4t authors: Chalkias, A.; Laou, E.; Kolonia, K.; Ragias, D.; Angelopoulou, Z.; Mitsiouli, E.; Kallemose, T.; Smith-Hansen, L.; Eugen-Olsen, J.; Arnaoutoglou, E. title: Elevated preoperative suPAR is a strong and independent risk marker for postoperative complications in high-risk patients undergoing major non-cardiac surgery (SPARSE) date: 2021-05-04 journal: nan DOI: 10.1101/2021.05.04.21256448 sha: c86a2c9859877144fb92bdcfefb5c49e04ddf363 doc_id: 270943 cord_uid: udynxh4t Background: Patients undergoing major surgery are often at risk of developing postoperative complications. We investigated whether the inflammatory biomarker suPAR can aid in identifying patients at high risk for postoperative complications, morbidity, and mortality. Methods: In this prospective observational study (ClinicalTrials.gov identifier: NCT03851965), peripheral venous blood was collected from consecutive adult patients scheduled for major non-cardiac surgery with expected duration [≥]2 hours under general anesthesia. Patients fulfilling the following inclusion criteria were included: age [≥]18 years and American Society of Anesthesiologists physical status I to IV. Plasma suPAR levels were determined using the suPARnostic quick triage lateral flow assay. The primary endpoint was post-operative complications defined as presence of any complication and/or admission to intensive care unit and/or mortality within the first 90 postoperative days. Results: Preoperative suPAR had an OR of 1.50 (95%CI 1.24-1.82) for every ng/ml increase (AUC 0.82, 95%CI: 0.72-0.91). When including age, sex, ASA score, CRP, and grouped suPAR in multivariate analysis, patients with suPAR between 5.5 and 10 ng/ml had an OR of 12.7 (CI: 3.6-45.5) and patients with suPAR>10 ng/ml had an OR of 20.7 (CI: 4.5-95.4) compared to patients with suPAR[≤]5.5 ng/ml, respectively. ROC analysis including age, sex, CRP levels, and ASA score and had an AUC of 0.69 (95%CI: 0.58-0.80). When suPAR was added to this Model, the AUC increased to 0.84 (0.74-0.93) (p=0.009). Conclusions: Preoperative suPAR provided strong and independent predictive value on postoperative complications in high-risk patients undergoing major non-cardiac surgery. It is estimated that over 300 million operations are performed every year worldwide, 1 with around 230 million of them being major surgeries. 2, 3 Although the perioperative event rate has declined over the past decades, adverse postoperative complications are a common cause of death and major morbidity in patients undergoing non-cardiac surgery. Complication rates vary among different countries but have been estimated at around 10%, 4 with 1 in every 13 deaths worldwide occurring within the first 30 days after surgery. 1 Postoperative complications increase admission to the intensive care unit (ICU) and hospital length of stay, having a significant impact on short-and long-term prognosis and healthcare costs. 2, 5 Risk for postoperative complications depends on many parameters, such as the patient's preoperative condition, comorbidities, or duration of the surgical procedure, and therefore, the traditional preoperative functional assessment is often insufficient for preoperative risk estimation. Various biomarkers have been suggested with the aim to improve risk stratification beyond that provided by risk scores. However, the most studied biomarkers are limited to predict cardiovascular adverse outcomes only. 6 A reliable prognostic biomarker that would be able to predict a variety of complications or improve current risk scores and could be incorporated into the process of risk stratification and optimization would be of great value in perioperative planning. Soluble urokinase plasminogen activator receptor (suPAR) is an immune mediator involved in numerous physiological and pathological pathways, including the plasminogen activating pathway, modulation of cell adhesion, and migration. 7, 8 The specific physiologic role of suPAR is unclear, but its levels in circulation reflect the aggregate activity of the uPAR system with respect to innate immune activity, All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 4, 2021. ; https://doi.org/10.1101/2021.05.04.21256448 doi: medRxiv preprint 5 proteolysis, and extracellular matrix remodeling. 8 The predictive ability of suPAR has been reported to be equal to or better than other scoring systems or biomarkers in patients presenting to the Emergency Department and is significantly associated with readmission, morbidity, and mortality. 8 These cumulative data suggest that high suPAR level is a marker of severe disease and may therefore provide benefit for the evaluation of surgical patients to improve risk stratification. The aim of the SPARSE study was to investigate whether the preoperative suPAR level can aid in identifying patients at high risk for postoperative complications, morbidity, and mortality following major noncardiac surgery. This was a prospective observational study conducted in the University Hospital of Larisa from February 2019 to September 2020 and designed in accordance with the declaration of Helsinki. Ethical approval for this study was provided by the Ethical Committee of the University Hospital of Larisa, Larisa, Greece (IRB no. 60580/11-12-2018). The study was registered at ClinicalTrials.gov (NCT03851965) and was performed according to national and international guidelines. Written informed consent was obtained from all patients. Consecutive patients who were scheduled to undergo elective major noncardiac surgery with expected duration ≥2 hours under general anesthesia were All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. Exclusion criteria were age <18 years, any infection within the previous four weeks, severe liver disease, patients on renal replacement therapy preoperatively, patients who had previously received a transplant, patients with allergies, inflammatory or immune system disorders, and/or connective tissue disease including rheumatoid arthritis, ankylosing spondylitis, and systemic lupus erythematosus, administration of steroid, antipsychotic, or anti-inflammatory/immunomodulatory medication within the previous 3 months, administration of opioids during the past week, asthma, obesity (BMI ≥30 kg m -2 ), mental disability or severe psychiatric disease, alcohol or other abuse, legal incapacity or limited legal capacity, and subjects currently involved in another study. Endotracheal intubation and anesthetic care were performed according to our institutional routine. Intravenous induction of general anesthesia included i.v. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 4, 2021. ; https://doi.org/10.1101/2021.05.04.21256448 doi: medRxiv preprint All patients were ventilated using a lung-protective strategy with tidal volume of 7 mL/kg, positive end-expiratory pressure of 6-8 cmH2O, and plateau pressures <30 cmH2O. Maintenance of general anesthesia included desflurane 1.0 MAC with 40% oxygen and 60% air, while intraoperative fraction of inspired oxygen was adjusted to maintain normoxia. Depth of anesthesia (bispectral index-BIS, Covidien, France) was monitored, with the target ranging between 40 and 60. 9,10 Normocapnia was maintained by adjusting the respiratory rate as needed, while normothermia (37 ºC) was maintained throughout the intraoperative period. All patients were operated by at least one consultant surgeon and a Professor of Surgery. Participants underwent sampling of peripheral venous blood immediately after arrival to the operating room and before induction of anesthesia. Blood samples drawn from all patients were collected in EDTA tubes and were centrifuged at 3.000 x g for 1 min. Plasma suPAR levels were then determined using the suPARnostic® quick triage lateral flow assay (ViroGates, Denmark). According to the manufacturer's instructions, there is no detectable impact on plasma suPAR concentration when comparing 1 and 10 min of centrifugation. The suPARnostic® Quick Triage, is an easy-to-use, quantitative test that is based on the lateral flow principle. The device consists of a nitrocellulose membrane with two immobilized antibody zones and a running buffer with gold particles. The quantitative results are read within 20 min by an optical aLF Reader (Qiagen, Germany) with a detection interval of 2-15 ng/mL suPAR. The primary endpoint was the presence of complications and/or admission to ICU and/or mortality within the first 90 postoperative days. We used the Clavien-Dindo All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. Data analysis was based on predefined data points on a prospective data collection form. The staff was blinded to measurements until the end of the study and all data were analyzed. Clinical monitoring throughout the study was performed to maximize protocol adherence, while an independent Data and Safety Monitoring research staff was monitored safety, ethical, and scientific aspects of the study. Data collection included demographics, ASA score, anesthesia parameters, general blood count, biochemistry profile, and C-reactive protein (CRP). Considering that the ASA score is not designed to predict mortality, has known inter-rater variation, and offers at least a moderate predictive ability for mortality in multiple surgical settings, we also included ACS-NSQIP and the Charlson Age-Comorbidity Index (Charlson score) in our analysis for the purposes of risk adjustment within research into perioperative outcomes. 15 All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The goal of the clinical data management plan was to provide high-quality data by adopting standardized procedures to minimize the number of errors and missing data, and consequently, to generate an accurate database for analysis. Remote monitoring was performed to signal early aberrant patterns, issues with consistency, credibility, and other anomalies. Any missing and outlier data values were individually revised and completed or corrected whenever possible. suPAR was used either as a continuous variable, log2 transformed, or grouped into three groups; ≤5.5 ng/ml; 5.5 -10 ng/ml; and >10 ng/ml, respectively. 16 We chose the cut-off of 5.5 ng/ml as this has been previously used in a study of preoperative suPAR levels and post-operative complications 16 and thus allows for comparison of previous findings. As the chosen cut-off gave a rather large group above 5.5 ng/ml, we chose a second cut-off at 10 ng/ml. There is no specific rationale for this second cutoff, except that suPAR in double digits is often referred to unusually high levels. Association of baseline risk scores (ASA score, ACS-NSQIP, and Charlson Comorbidity Index), CRP(log10), and suPAR with primary endpoint (complications and/or admission to ICU and/or mortality within the first 90 postoperative days) was analyzed with logistic regression models. Both univariable models and multivariable models including age, sex, ASA score, CRP, and suPAR in a single model were fitted. SuPAR was included as continues variable in the univariable analysis and as the 3-level categorical variable in the multivariable analysis. Odds Ratio (OR) with 95% confidence intervals (CI) was reported for the logistic regression models. ROC analysis was carried out using continuous variables to evaluate the predictive level of the baseline risk scores, CRP, and suPAR in relation to the primary endpoint. Analysis was All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. 7.15 HF7 (7.100.5.6177) (64-bit). The main statistics procedure used is proc logistic. Of the 100 patients undergoing surgery, 68 (68%) were men and 32 (32%) were Table 1 . Postoperative complications are depicted in Table 2 All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. In the multivariate logistic regression analysis, suPAR was included as a 3-level variable (as shown in Table 1 ): patients with suPAR ≤5.5 ng/ml (n=27), patients with suPAR between 5.5 and 10 ng/ml (n=47), and patients with suPAR >10 ng/ml (n=26). When including age, sex, ASA score, CRP, and grouped suPAR in multivariate analysis, patients with suPAR level between 5.5 and 10 ng/ml had an OR of 12.7 (CI: 3.6-45.5) and patients with suPAR >10 ng/ml had an OR of 20.7 (CI: 4.5-95.4) when compared to patients with suPAR ≤5.5 ng/ml, respectively. Table 1 ), which significantly improved the prediction (p=0.009). The ROC curves are shown in Figure 2 . All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. In this prospective observational study, we report that preoperative suPAR provides strong and independent association with postoperative complications in highrisk patients undergoing major non-cardiac surgery. For every ng/ml increase, a patient has 50% increased odds of developing postoperative complications. Furthermore, the addition of suPAR to a model including age, sex, CRP levels, and ASA score significantly improved the prediction of postoperative complications. Appropriate risk assessment plays an integral role in optimizing perioperative management to achieve best possible outcomes. However, failure to identify patients at a high risk remains a significant concern and is associated with low-quality postoperative care and increased morbidity and mortality. 17, 18 Risk scores and risk prediction models are used to make a preoperative assessment, but they utilize various predictors and intend to predict different outcomes. Similarly, preoperative biomarkers may improve risk stratification, but their use is currently limited to predicting cardiac complications (e.g., high sensitivity Troponin T or natriuretic peptides). 15 On the other hand, preoperative resources, such as scheduled ICU admission, would be more appropriately allocated if patient risk could be better assessed. Previous studies have reported that patients undergoing major non-cardiac surgery are at high risk of complications and death, [19] [20] [21] Nevertheless, the development of a universal, rapidly administered, risk assessment tool specific to major surgeries has so far been elusive. Systemic inflammation plays a major role in the development of cardiovascular and other diseases and its mediators directly injure the cells and/or modulate their response to damage. 22, 23 Consequently, the preoperative inflammatory status can be a major contributor to postoperative organ injury and therefore it is very important for All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 4, 2021. ; https://doi.org/10.1101/2021.05.04.21256448 doi: medRxiv preprint risk stratification. 22, 24 In addition, preoperative neuroendocrine responses to stress can modify the immune function and are associated with adverse outcomes, 25-28 while several drugs may induce inflammation or exert significant anti-inflammatory properties. [29] [30] [31] Therefore, preoperative suPAR levels may also assist in measuring inflammation, identifying a proinflammatory, inflammatory, or an immunosuppressive status, which can influence short-and long-term outcome and/or disease progression. Of note, smoking cessation has been reported to lead to a significant (around 1 ng/ml) drop in suPAR within 4 weeks, which in conjunction with the results presented in the current study, may in part explain the importance of smoking cessation before surgery. 32, 33 Also, several proinflammatory conditions are associated with high suPAR levels, such as cardiovascular, autoimmune, and lung diseases, atherosclerosis, cancer, or heart failure, and a high suPAR level has been associated with poor prognosis and complications after surgery in other cohorts. 8, 16, 34, 35 Several studies have assessed CRP as a preoperative marker, reporting that it may contribute to postoperative complications. 36, 37 However, CRP usually rises in acute inflammatory conditions and due to its short half-life, it is mainly used as a serum marker of acute inflammatory states. 37 In our study, CRP levels were not associated with postoperative complications, which supports the findings of other authors and the NICE guidelines that do not recommend its use as a preoperative marker. 38,39 In contrast, we found that for every ng/ml increase in preoperative suPAR, the patient has 50% increased odds of developing postoperative complications. The superiority of suPAR as a prognostic biomarker seems to be largely based on its cellular and molecular effects, with its levels in circulation reflecting the aggregate activity of the uPAR system with respect to innate immune activity and cellular injury. 8, [40] [41] [42] Of note, suPAR is a more stable molecule, both in vivo and in vitro, which makes it a more All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 4, 2021. ; https://doi.org/10.1101/2021.05.04.21256448 doi: medRxiv preprint reliable biomarker for reflecting the overall health condition and state of chronic immune activation of the patient. 43 On the contrary, CRP is synthesized by the liver only in response to mediators released by macrophages and other cells in acute conditions. Importantly, we found that when including age, sex, ASA score, CRP, and grouped suPAR in multivariate analysis, patients with suPAR level between 5.5 and 10 ng/ml had an OR of 12.7, which increased to 20.7 in patients with suPAR >10 ng/ml. Today, the ASA classification remains the main tool for risk stratifying surgical patients. 15, 16 However, it has been criticized for its subjectivity, inter-observer variability, and inconsistency. 44 Also, the ASA classification is related to the anesthesiologist's knowledge and may be less accurate. 45 In a previous study, suPAR was significantly associated with the occurrence of postoperative complications and was equally as good as the ASA classification in predicting endpoints. Also, the hazard ratio for 90-day postoperative mortality was 2.5 (95% CI: 1.6-4.0) for every doubling of suPAR level after adjusting for age, sex, and ASA classification. 16 When these authors combined ASA score and suPAR level, they reported an improved prediction of mortality or complications within 90 days after surgery. 16 Our study shows a significantly increased prediction of postoperative complications and further strengthen the potential of suPAR as a preoperative risk marker. Based on our findings, and the findings of others, 16, 45, 46 suPAR may improve the accuracy of ASA score and could also be used as a central parameter in enhanced recovery after surgery protocols. Of note, the other preoperative risk assessment models used in our study have significant limitations. 15 The ACS-NSQIP surgical risk calculator can be used for predicting major adverse cardiovascular events, but external validations have been inconsistent and tend to favor a conclusion of inadequate performance. 16, 47 The Charlson scores was not developed to evaluate risk in surgical patients, although the later has been used for this All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. 15 These scores also require consideration of numerous variables and are complicated and time-consuming. 16, 47 The study has several strengths. It is a well-designed, prospective observational study that relied on collection of clinical, laboratory, and outcome data, capturing a diverse surgical population. Data collection was systematic and all consecutive patients were enrolled. Another strength is the inclusion of many patients with ASA classifications III and IV, which enhances the discriminatory capabilities of suPAR. Moreover, we assessed suPAR as a part of risk models, which included other risk scores. The main limitation is that it is a single-center study and should be reproduced in a multicenter study to improve general applicability. The number of patients may be relatively small for the different types of surgical interventions, but we revealed important associations and results that can be used in future studies. Future studies should be larger to include more variables in multivariate models. Considering that suPAR levels remain uninfluenced of the surgical trauma, 48 the use of suPAR in the preoperative stratification process, especially of high-risk patients, represents a promising novel approach. 49 Preoperative suPAR has a strong and independent association with postoperative complications in high-risk patients undergoing major non-cardiac surgery. For every ng/ml increase, a patient has 50% increased odds of developing postoperative complications. The addition of suPAR to other parameters significantly improved the prediction of postoperative complications. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 4, 2021. ; https://doi.org/10.1101/2021.05.04.21256448 doi: medRxiv preprint Eugen-Olsen provided expert interpretation of the findings. Dr. Athanasios Chalkias wrote the first draft of the manuscript. All coauthors provided critical revisions to the manuscript. All coauthors had full access to the data and take responsibility for the integrity and accuracy of the data analysis. All authors approved the final version of the manuscript. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. Peri-operative cardiac biomarker screening: a narrative review Pre-operative cardiac optimisation: a directed review Cardiac biomarkers and risk assessment in patients undergoing major non-cardiac surgery: time to revise the guidelines? Safe Surgery Saves Lives Study Group. A surgical safety checklist to reduce morbidity and mortality in a global population Rehospitalizations among patients in the Medicare fee-for-service program Authors/Task Force Members. 2014 ESC/ESA Guidelines on non-cardiac surgery: cardiovascular assessment and management: The Joint Task Force on non-cardiac surgery: cardiovascular assessment and management of the European Society of Cardiology (ESC) and the European Society of Anaesthesiology (ESA) Soluble Urokinase Plasminogen Activator Receptor: A Biomarker for Predicting Complications and Critical Care Admission of COVID-19 Patients Hayek SS; International Study of Inflammation in COVID-19. Soluble Urokinase Receptor (SuPAR) in COVID-19-Related AKI Cumulative duration of "triple low" state of low blood pressure, low bispectral index, and low minimum alveolar concentration of volatile anesthesia is not associated with increased mortality Association between intraoperative electroencephalographic suppression and postoperative mortality Experiences with the standardized classification of surgical complications (Clavien-Dindo) in general surgery patients The Comprehensive Complication Index (CCI®): Added Value and Clinical Perspectives 3 Years "Down the Line Comprehensive Complication Index Predicts Cancer-specific Survival After Resection of Colorectal Metastases Independent of RAS Mutational Status Comprehensive Complication Index Predicts Cancer-Specific Survival of Patients with Postoperative Complications after Curative Resection of Gastric Cancer Pre-operative evaluation of adults undergoing elective noncardiac surgery: Updated guideline from the European Society of Anaesthesiology Soluble Urokinase Plasminogen Activator Receptor (suPAR) as an Added Predictor to Existing Preoperative Risk Assessments Review of risk assessment tools to predict morbidity and mortality in elderly surgical patients Identification and characterisation of the high-risk surgical population in the United Kingdom Postoperative complications and implications on patient-centered outcomes Incidence and significance of postoperative complications occurring between discharge and 30 days: a prospective cohort study Patient reporting of complications after surgery: what impact does documenting postoperative problems from the perspective of the patient using telephone interview and postal questionnaires have on the identification of complications after surgery? Preoperative systemic inflammation and perioperative myocardial injury: prospective observational multicentre cohort study of patients undergoing non-cardiac surgery Patients with colorectal cancer are characterized by increased concentration of fecal hb-hp complex, myeloperoxidase, and secretory IgA lymphocyte and platelet ratio as a predictor of postoperative acute kidney injury in major abdominal surgery The immune-suppressive nature of pain The effects of psychological stress on humans: increased production of proinflammatory cytokines and a Th1-like response in stress-induced anxiety A mechanism converting psychosocial stress into mononuclear cell activation Beta-blockers are associated with lower C-reactive protein concentrations in patients with coronary artery disease Statins are associated with a reduced incidence of perioperative mortality in patients undergoing major noncardiac vascular surgery Drug-induced acute interstitial nephritis Plasma suPAR is lowered by smoking cessation: a randomized controlled study Smoking and timing of cessation on postoperative pulmonary complications after curative-intent lung cancer surgery Prognostic value of intact and cleaved forms of the urokinase plasminogen activator receptor in a retrospective study of 518 colorectal cancer patients Diagnostic and prognostic significance of CA IX and suPAR in gastric cancer High preoperative C-reactive protein level is a risk factor for acute exacerbation of interstitial lung disease after non-pulmonary surgery Predictive value of preoperative serum C-reactive protein for recurrence after definitive surgical repair of enterocutaneous fistula doi: medRxiv preprint 38. Padayachee L, Rodseth RN, Biccard BM. A meta-analysis of the utility of Creactive protein in predicting early, intermediate-term and long term mortality and major adverse cardiac events in vascular surgical patients Clinical utility of perioperative C-reactive protein testing in general surgery Regulation of cell signalling by uPAR Structure of human urokinase plasminogen activator in complex with its receptor Soluble urokinase plasminogen activator receptor measurements: influence of sample handling The ASA Physical Status Classification: inter-observer consistency No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted suPAR is associated with risk of future acute surgery and post-operative mortality in acutely admitted medical patients An Examination of American College of Surgeons NSQIP Surgical Risk Calculator Accuracy suPAR remains uninfluenced by surgery in septic patients with bloodstream infection Borderline resectable pancreatic cancer. Challenges and controversies Age (years), median Age-Comorbidity Index p-values for sex is Pearson Chi 2 , calculated in SAS-Proc Freq All other p-values is Kruskal-Wallis Chi 2 , calculated in SAS-Proc npar1way Other types include endocrinological (n=1), thoracic (n=3), gastrointestinal and gynecological (n=1), and thyroidectomy (n=1) The authors would like to thank the medical and nursing stuff of the Department of Anesthesiology, University Hospital of Larisa, for their assistance during the study period.Funding: No funding received. All rights reserved. No reuse allowed without permission.(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint this version posted May 4, 2021. ; https://doi.org/10.1101/2021.05.04.21256448 doi: medRxiv preprint All rights reserved. No reuse allowed without permission.(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint this version posted May 4, 2021. ; https://doi.org/10.1101/2021.05.04.21256448 doi: medRxiv preprint All rights reserved. No reuse allowed without permission.(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint this version posted May 4, 2021. ; https://doi.org/10.1101/2021.05.04.21256448 doi: medRxiv preprint All rights reserved. No reuse allowed without permission.(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint this version posted May 4, 2021. ; https://doi.org/10.1101/2021.05.04.21256448 doi: medRxiv preprint All rights reserved. No reuse allowed without permission.(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint this version posted May 4, 2021. ; https://doi.org/10.1101/2021.05.04.21256448 doi: medRxiv preprint All rights reserved. No reuse allowed without permission.(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. Figure 2 . ROC curve for Model 1 (Age, sex, CRP, and ASA score) and Model 2 (Age, sex, CRP, ASA score, and suPAR). Model 2 was significantly better than Model 1.All rights reserved. No reuse allowed without permission.(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint this version posted May 4, 2021. ; https://doi.org/10.1101/2021.05.04.21256448 doi: medRxiv preprint Table 1 . Baseline characteristics and distribution of baseline parameters according to suPAR predefined levels All suPAR ≤ 5.5 ng/ml 5.5 ng/ml < suPAR ≤ 10 ng/ml 10 ng/ml < suPAR p value N=100 n=27 n=47 n=26